Pirfenidone for Glottic Stenosis: Topical Versus Systemic Routes in a Bleomycin Rat Model

OBJECTIVE: Laryngeal stenosis is a fibroinflammatory disease of dysregulated wound healing and excessive collagen deposition lacking effective pharmacological prophylaxis. Pirfenidone is an antifibrotic agent. We compared topical versus systemic pirfenidone for preventing glottic stenosis in a bleomycin-induced rat model. METHODS: Thirty male Wistar rats underwent endoscopic bleomycin-induced glottic and subglottic injury and were randomized to topical pirfenidone (10 mg per application; Days 0, 3, 7, 14), systemic pirfenidone (40 mg/kg/day orally, 14 days), or untreated control. After 4 weeks, larynges were harvested for macroscopic stenosis grading by two blinded observers and semi-quantitative (0-3) histopathological and immunohistochemical scoring. Groups were compared with Fisher's exact and Kruskal-Wallis tests. RESULTS: Twenty-five animals (control n = 7; systemic n = 9; topical n = 9) completed the study. Five died (3 control, 1 per treated group; log-rank p = 0.386). Macroscopic stenosis differed among groups (p = 0.015), being reduced in systemic (p = 0.014) and topical (p = 0.010) groups versus control, with no difference between routes (p = 0.531). A sensitivity analysis assigning the deaths the worst outcome (n = 30) gave the same result (p = 0.011). Submucosal fibrosis (p = 0.005) and collagen-1 (p = 0.001) differed overall; pairwise reductions were significant only for systemic versus control. Epithelial damage, inflammation, TGF-β1, α-SMA, and CD4 did not differ significantly. CONCLUSION: Both routes significantly reduced macroscopic glottic stenosis, with no significant difference between them, whereas antifibrotic effects on fibrosis and collagen-1 were confined to systemic administration. Topical pirfenidone warrants further study. LEVEL OF EVIDENCE: N/A (basic science/preclinical animal study).